Pathogenic poxviruses such as variola virus and monkeypox virus pose a dangerous threat to today's largely unimmunized population, while attenuated poxviruses hold great promise as vaccine vectors. The need for both anti-poxvirus therapies and better poxvirus-based vaccines demands a deeper understanding of how poxviruses modulate the host immune responses. The focus of this proposal is on a potent interleukin-18 (IL- 18) inhibitor that is secreted by a wide variety of poxviruses, including variola virus, monkeypox virus and vaccinia virus. IL-18 is a pleiotropic cytokine that enhances both the innate and acquired immunity [1, 2]. It protects against microbial infection and tumors in murine models. Many poxviruses express an IL-18 binding protein (IL-18BP) that binds to IL-18 with high affinity and inhibits IL-18 mediated immune responses [3-5]. The central hypotheses behind this proposal are that poxvirus IL-18BP greatly affects poxvirus pathogenicity and immunogenicity and that a comprehensive understanding of IL-18BP functioning mechanism and in vivo effects will lead to new therapies for poxvirus diseases and better poxvirus- based vaccines. Our specific aims are: 1. To further determine the molecular mechanism by which IL-18BP binds and inhibits IL-18. A detailed understanding of the specific interactions between IL-18, IL-18BP and IL-18 receptor at the molecular level will greatly benefit the development of specific inhibitors against IL-18BP and IL-18 for the treatment of infectious and inflammatory diseases. 2. To develop inhibitors against poxvirus IL-18BP and evaluate the effects of these inhibitors at reducing poxvirus pathogenicity. To determine the spatial requirement of poxvirus IL-18BP in poxvirus pathogenesis. 3. To determine the role of IL-18BP in immunogenicity of poxvirus-based vaccine. This will allow a better understanding of the role of IL-18 in the development of protective immune responses and facilitate the development of a safer and more immunogenic vaccine vector. PUBLIC HEALTH RELEVANCE: The need for both anti-poxvirus therapies and better poxvirus-based vaccines demands a deeper understanding of how poxviruses modulate the host immune responses. The focus of this proposal is on a potent interleukin-18 (IL-18) inhibitor that is secreted by a wide variety of poxviruses, including variola virus, monkeypox virus and vaccinia virus. A comprehensive understanding of IL-18BP functioning mechanism and in vivo effects will lead to new therapies for poxvirus diseases and better poxvirus-based vaccines.